3-Oxo-hexahydro-1<i>H</i>-isoindole-4-carboxylic Acid as a Drug Chiral Bicyclic Scaffold: Structure-Based Design and Preparation of Conformationally Constrained Covalent and Noncovalent Prolyl Oligopeptidase Inhibitors

Mariaule, Gaëlle; Cesco, Stéphane De; Airaghi, Francesco; Kurian, Jerry; Schiavini, Paolo; Rocheleau, Sylvain; Huskić, Igor; Auclair, Karine; Mittermaier, Anthony; Moitessier, Nicolas

doi:10.1021/acs.jmedchem.5b01296

Cited by 33 publications

(41 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human prolyl oligo peptidase was purified as described in Supplementary Methods section 33 and dialyzed in a buffer containing 20 mM sodium phosphate, pH 8, 150 mM sodium chloride, and 10% (v/w) glycerol, prior to flash freezing in ~300 µL aliquots at ≈1–4 μM in liquid nitrogen and storing at −80 °C. Kinetic experiments were carried out with freshly thawed POP in the same buffer above with BSA (0.5 mg/mL) added to help stabilize POP.…”

Section: Methodsmentioning

confidence: 99%

Rapid measurement of inhibitor binding kinetics by isothermal titration calorimetry

et al. 2018

Self Cite

View full text Add to dashboard Cite

Although drug development typically focuses on binding thermodynamics, recent studies suggest that kinetic properties can strongly impact a drug candidate’s efficacy. Robust techniques for measuring inhibitor association and dissociation rates are therefore essential. To address this need, we have developed a pair of complementary isothermal titration calorimetry (ITC) techniques for measuring the kinetics of enzyme inhibition. The advantages of ITC over standard techniques include speed, generality, and versatility; ITC also measures the rate of catalysis directly, making it ideal for quantifying rapid, inhibitor-dependent changes in enzyme activity. We used our methods to study the reversible covalent and non-covalent inhibitors of prolyl oligopeptidase (POP). We extracted kinetics spanning three orders of magnitude, including those too rapid for standard methods, and measured sub-nM binding affinities below the typical ITC limit. These results shed light on the inhibition of POP and demonstrate the general utility of ITC-based enzyme inhibition kinetic measurements.

show abstract

Section: Methodsmentioning

confidence: 99%

Rapid measurement of inhibitor binding kinetics by isothermal titration calorimetry

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The binding poses are ranked by the RankScore and MatchScore algorithms. This methodology was used to identify novel covalent inhibitors of prolyl oligopeptidase that exhibited high selectivity and affinity to Ser554[53,54,55].Del Rio et al developed a computational workflow for evaluating the binding of a covalent modifier to a protein [56]. A database of kinase proteins with non-covalently-bound structures was constructed from the Protein Data Bank.…”

mentioning

confidence: 99%

Modeling covalent-modifier drugs

Awoonor-Williams

Walsh

Rowley

2017

Preprint

View full text Add to dashboard Cite

In this review, we present a summary of how computer modeling has been used in the development of covalent modifier drugs. Covalent modifier drugs bind by forming a chemical bond with their target. This covalent binding can improve the selectivity of the drug for a target with complementary reactivity and result in increased binding affinities due to the strength of the covalent bond formed. In some cases, this results in irreversible inhibition of the target, but some targeted covalent inhibitor (TCI) drugs bind covalently but reversibly. Computer modeling is widely used in drug discovery, but different computational methods must be used to model covalent modifiers because of the chemical bonds formed. Structural and bioinformatic analysis has identified sites of modification that could yield selectivity for a chosen target. Docking methods, which are used to rank binding poses of large sets of inhibitors, have been augmented to support the formation of protein-ligand bonds and are now capable of predicting the binding pose of covalent modifiers accurately. The pK a 's of amino acids can be calculated in order to assess their reactivity towards electrophiles. QM/MM methods have been used to model the reaction mechanisms of covalent modification. The continued development of these tools will allow computation to aid in the development of new covalent modifier drugs.

show abstract

“…NMR Spectroscopy and X‐ray Crystallography: We used the procedures reported in ref https://www.ccdc.cam.ac.uk/services/structures?id=doi:10.1002/ejoc.201601457. 1439240 (for 5a ), 1439241 (for 5b ), and 1492626 (for 8c ) contain the supplementary crystallographic data for this paper.…”

Section: Methodsmentioning

confidence: 99%

Highly Regioselective Monoacylation of Unprotected Glucopyranoside Using Transient Directing‐Protecting Groups

et al. 2017

Self Cite

View full text Add to dashboard Cite

The regioselective functionalization of monosaccharides is notoriously achieved using metal catalysis, lengthy synthetic strategies requiring protection/deprotection, various enzymes, or other methods that target cis‐diols (and thus cannot be used with glucopyranose derivatives), In this paper, we report a new method using selected boronic acids as temporary protecting groups, and describe its application to the regioselective functionalization of methyl α‐d‐glucopyranoside, the most difficult monosaccharide to functionalize regioselectively. Generally, reactions of glucopyranosides may lead to a plethora of mono‐ and polyfunctionalized derivatives, yet our method gave the 3‐O‐acetylated, 2‐O‐benzoylated, and 2‐O‐pivaloylated derivatives of methyl α‐d‐glucopyranoside as major products. We focused on the use of recyclable and green temporary protecting groups (in a one‐pot reaction) and on the modulation of the intramolecular hydrogen‐bonding network using selected arylboronic acids. A complete scalable procedure leading to a single regioisomer from unprotected methyl α‐d‐glucopyranoside is presented.

show abstract

3-Oxo-hexahydro-1H-isoindole-4-carboxylic Acid as a Drug Chiral Bicyclic Scaffold: Structure-Based Design and Preparation of Conformationally Constrained Covalent and Noncovalent Prolyl Oligopeptidase Inhibitors

Cited by 33 publications

References 43 publications

Rapid measurement of inhibitor binding kinetics by isothermal titration calorimetry

Rapid measurement of inhibitor binding kinetics by isothermal titration calorimetry

Modeling covalent-modifier drugs

Highly Regioselective Monoacylation of Unprotected Glucopyranoside Using Transient Directing‐Protecting Groups

Contact Info

Product

Resources

About